Hallucinogenic/psychedelic 5HT2A receptor agonists as rapid antidepressant therapeutics: Evidence and mechanisms of action

Major depressive disorder affects many people worldwide and current antidepressants often work slowly, have side effects, and fail about a third of patients. Psychedelics such as LSD, psilocybin, and ayahuasca are among the few compounds with recent human evidence of fast-acting antidepressant effects. Studies from the 1950s to 1970s reported antidepressive and anxiolytic effects, which modern trials are confirming (LSD, one trial; psilocybin, five trials; ayahuasca, two trials). These drugs appear to work primarily by activating serotonin receptors, especially the 5-HT2A receptor. The promising but limited evidence of safety and efficacy has encouraged further research into psychedelics for depression.

Study at a glance

Abstract

Major depressive disorder (MDD) is among the most prevalent mental health disorders worldwide, and it is associated with a reduced quality of life and enormous costs to health care systems. Available drug treatments show low-to-moderate response in most patients, with almost a third of patients being non-responders (treatment-resistant). Furthermore, most currently available medications need several weeks to achieve therapeutic effects, and the long-term use of these drugs is often associated with significant unwanted side effects and resultant reductions in treatment compliance. Therefore, more effective, safer, and faster-acting antidepressants with enduring effects are needed. Together with ketamine, psychedelics (or classic or serotoninergic hallucinogens) such as lysergic acid diethylamide (LSD), psilocybin, and ayahuasca are among the few compounds with recent human evidence of fast-acting antidepressant effects. Several studies in the 1950s to 1970s reported antidepressive and anxiolytic effects of these drugs, which are being confirmed by modern trials (LSD, one trial; psilocybin, five trials; ayahuasca, two trials). The effects of these drugs appear to be produced primarily by their agonism at serotonin (5-hydroxytryptamine, 5-HT) receptors, especially the 5-HT 2A receptor. Considering the overall burden of MDD and the necessity of new therapeutic options, the promising (but currently limited) evidence of safety and efficacy of psychedelics has encouraged the scientific community to explore more fully their beneficial effects in MDD.